Processing of VEGF-A by matrix metalloproteinases regulates bioavailability and vascular patterning in tumors

By Sunyoung Lee, Shahla M. Jilani, G. Nikolova, D. Carpizo, M. Luisa Iruela-Arispe. Journal of Cell Biology, 2005

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Vascular endothelial growth factor (VEGF) is a critical mediator of blood vessel formation during development and in pathological conditions. In this study, we demonstrate that VEGF bioavailability is regulated extracellularly by matrix metalloproteinases (MMPs) through intramolecular processing. Specifically, we show that a subset of MMPs can cleave matrix-bound isoforms of VEGF, releasing soluble fragments. We have mapped the region of MMP processing, have generated recombinant forms that mimic MMP-cleaved and MMP-resistant VEGF, and have explored their biological impact in tumors. Although all forms induced similar VEGF receptor 2 phosphorylation levels, the angiogenic outcomes were distinct. MMP-cleaved VEGF promoted the capillary dilation of existent vessels but mediated a marginal neovascular response within the tumor. In contrast, MMP-resistant VEGF supported extensive growth of thin vessels with multiple and frequent branch points. Our findings support the view that matrix-bound VEGF and nontethered VEGF provide different signaling outcomes. These findings reveal a novel aspect in the regulation of extracellular VEGF that holds significance for vascular patterning.

Subfields: Cancer Research, Immunology and Allergy, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/6b5489fb43c3f6c6b086aca6a127aeff7dc24f59

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Citations in the corpus

Molecular regulation of angiogenesis and lymphangiogenesis (2007, background): “The proteolytic release of pericellular matrix-bound VEGF isoforms is an important regulator of VEGF bioavailability and blood-vessel patternin”
Neutrophil Elastase-Mediated Degradation of IRS-1 Accelerates Lung Tumor Growth (2010, background): “However, upon activation, neutrophils translocate neutrophil elastase to the cell surface and secrete small amounts of the enzyme from individual granule”
Myocardial matrix remodeling and the matrix metalloproteinases: influence on cardiac form and function. (2007, background): “There is emerging evidence to suggest that MMPs can also degrade nonmatrix substrates such as cytokines, bioactivate peptides, and growth factors, which in turn would affect a number of biological processes within the myocardium (125, 170, 210, 213, 222, 280, 306, 309, 318, 413, 435, 463, 500, 523).”
Blood-brain barrier pathophysiology in traumatic brain injury (2011, background): “Thirteen MMPs are secreted as latent zymogens and, therefore, need to undergo a complex process of activation to exhibit full enzymatic activity [98].”
Autocrine VEGF signaling is required for vascular homeostasis. (2007, neutral): “VEGFR2 phosphorylation was determined by immunoprecipitating cell lysates with 4G-10 antibody (Upstate, NY) and analyzing by Western blot with anti-phosphotyrosine antibody (Cell signaling, MA) as described (Lee et al., 2005).”
Vascular endothelial growth factor (VEGF) signaling in tumor progression. (2007, background): “While native glycosylated VEGF-189 has a molecular weight of 52 kDa, their studies showed that VEGF-189 is released from mutant cells as a 40-kDa form that is generated by endogenous protease activity.”
Matrix Metalloproteinases: Regulators of the Tumor Microenvironment (2010, background): “In addition, the direct cleavage of matrix-bound VEGF by MMP-3, -7, -9, or -16 results in modified VEGF molecules with altered bioavailability, which changes the vascular patterning of tumors in vivo (Lee et al., 2005).”
Interstitial flow and its effects in soft tissues. (2007, background): “The various other enzymes work on specific matrix components and morphogens by different mechanisms such as denaturing binding sites (88), cleaving a portion of the bound morphogen (97), or cleaving the binding molecule itself, leaving a soluble morphogen with a portion of the binding molecule still”
Matrix metalloproteinases and the regulation of tissue remodelling (2007, background): “Truncated VEGF has different effects on tumour blood vessels than does uncleavable VEGF; truncated VEGF increases vessel diameter, whereas uncleavable VEGF increases vessel sproutin”